Oxiran carboxylic acids for the treatment of diabetes

ABSTRACT

The invention relates to novel arylalkyl- or aryloxyalkyl-substituted oxiranecarboxyclic acids of the general formula I  
                 
 
     in which Ar, R 3 , Y and n are as defined in the description, and also to medicaments comprising them and to their use for the treatment and prophylaxis of the disorders mentioned in the description [in claim 4] which are caused by disturbances of glucose and/or lipid metabolism, such as, for example diabetes type 2, and other insulin-resistant conditions.

TECHNICAL FIELD

[0001] This invention relates to oxirane carboxylic acid derivativeexpressed by the following formula (1), its manufacturing method andantidiabetic agent containing it.

[0002] Wherein:

[0003] A is one selected from the radicals expressed by the following(i), (ii), (iii) and (iv);

[0004] R₁ represents a lower alkyl;

[0005] (wherein, R₂˜R₁₃ represent independently hydrogen, halogen,alkoxy, lower alkyl, hydroxy, alkenyl, alkynyl, cyano or amino group; Bis independently nitrogen or carbon; X is oxygen or sulfur; n denotes 0,1 or 2).

BACKGROUND OF ART

[0006] The diabetic patients tend to suffer from some disorders such asinhibition of glucose uptake, inhibited glycolysis and increasingbeta-oxidation of fatty acid in their peripheral tissues, which causethe use of fat for their body's energy source instead of glucose andlead to some diseases such as hyperglycemia, hyperlipidemia andhyperketonemia.

[0007] The beta-oxidation of fat in diabetic patients occurs in amitochondrial substrate. Carnitine palmitoyl transferase I (CPT I) is anenzyme to transport a higher fatty acid from cytoplasm to amitochondrial substrate, and plays an vital role in limiting thebeta-oxidation rate.

[0008] Therefore, CPT I inhibitors will be utilized as an effectiveantidiabetic agent in that they may inhibit the beta-oxidation of higherfatty acids, increase the availability of glucose and exert thehypoglycemic, hypolipidemic and hypoketonemic effects.

[0009] The typical compounds belonging to the above mentioned CPT Iinhibitors include palmoxirate, clomoxir(POCA) and etomoxir, and thesecompounds are characterized in that all of them have oxirane carboxylicacid in their most active site.

[0010] The inhibitory action of these oxirane carboxylic acidderivatives against the CPT I has yet to be elucidated up to now but ithas been assumed that since these derivatives have the stable covalentbonding in the active sites of CPT I within cytoplasm, their inhibitionaction against the CPT I may contributed to the treatment of diabetes.Therefore, a possible mode of action is that when some nucleophilicsubstance at the active site of CPT I initiates to attack the epoxidering structure of oxirane carboxylic acid derivatives, the openedepoxide ring forms a new hydroxyl group, and at the same time CPT I andoxirane carboxylic acid derivative is covalently bonded, thus the CPT Iactivity is inhibited.

[0011] However, the phase II clinical trials of etomoxir had not beencontinued owing to some side effects associated with prolongedadministration, such as enlarged heart and toxicity in the liver, butits cause has not been explicitly known up to now.

DISCLOSURE OF INVENTION

[0012] Based on the mechanism that these oxirane carboxylic acidderivatives have exerted inhibitory actions against the CPT I, theinventor et al. have extensively studied to develop some promisingcompounds with blood glucose lowering effects, thus showing remarkableantidiabetic activities and less side effects. To this end, the inventoret al. have come to know that as a result of screening various kinds ofderivatives having oxirane carboxylic acid positioned at their mostactive sites, oxirane carboxylic acid derivative of the formula 1 withopened epoxy ring at oxirane structure has proven to have an excellentantidiabetic activity and less side effects. In consequence, thisinvention has been completed.

[0013] An object of this invention is to provide oxirane carboxylic acidderivative expressed by the following formula 1.

[0014] Wherein:

[0015] A is one selected from the radicals expressed by the following(i), (ii), (iii), (iv) and (v);

[0016] R₁ represents a lower alkyl;

[0017] (wherein, R₂˜R₁₃ represent independently hydrogen, halogen,alkoxy, lower alkyl, hydroxy, alkenyl, alkynyl, cyano or amino group; inparticular, R₂ is hydrogen, bromine or chlorine; R₃ is hydrogen, methyl,n-buthyl, chlorine or methoxy; R₄ is hydrogen or methoxy; R₅ is hydrogenor bromine; R₆, R₇, R₉, R₁₂ are hydrogen; R₈ is hydrogen, methyl,chlorine or methoxy; R₁₀ is hydrogen or chlorine; R₁₁, R₁₃ arepreferably methyl; B is independently nitrogen or carbon; X is oxygen orsulfur; n denotes 0, 1 or 2).

[0018] Another object of this invention is to provide some compoundsexpressed by the above mentioned formula 1.

[0019] Another object of this invention is also to provide anantidiabetic agent containing some compounds expressed by the abovementioned formula 1.

[0020] The compound of the formula I according to this invention may beprepared by the following reaction scheme 1:

[0021] (wherein A and R₁ are the same as defined above.)

[0022] The aforementioned reaction scheme is explained as follows:

[0023] a) 1,6-hexanediol of the structural formula 2, a well knownsubstance and starting material, is treated with sodium hydride as abase to synthesize 6-benzyloxy-1-hexanol of the structural formula 3with substituted benzyl ring;

[0024] b) The compound of the formula 3 is tosylated to furnish thecompound of the structural formula 4;

[0025] c) The compound of the structural formula 4 is reacted withdimalonate to synthesize dialkyl-6-benzoxyhexylmalonate of the generalformula 5;

[0026] d) The compound of the general formula 5 is hydrolyzed usingpotassium hydride to furnish the compound of the general formula 6;

[0027] e) Eschernmorser's salt is added to the compound of the generalformula 6 to synthesize the alpha, beta-unsaturated ester of the generalformula 7;

[0028] f) The compound of the general formula 7 is catalyzed by osmiumtetroxide to give the compound of the general formula 8;

[0029] g) The compound of the general formula 8 is further tosylated tosynthesize alkyl-2-hydroxy-3-(4-methylbenzenesulfoxy)-2-(6-benzoxy)hexylpropionic acid of the general formula 9;

[0030] h) The compound of the general formula 9 is treated withpotassium carbonate as a base to givealkyl-2-(6-benzoxy)hexyloxirane-2-carboxylic acid of the general formula10, followed by the intermolecular cyclic reaction;

[0031] i) The compound of the general formula 10 is hydrogenated to givethe compound of the general formula 11 with its benzyl groupdeprotected;

[0032] j) The compound of the general formula 11 is treated with DCC,DMAP and methane dichloride to give oxirane carboxylic acid derivativeof the formula 1, a desired compound, via esterification, etherificationor amidofication with AH of the general formula.

[0033] Meantime, in case where A, a substituent of the final reactionprocess, is a radical (i) or (ii), the ester linkage of a final productis relatively strong in its reactability and to increase the yield, itis preferred to perform the substitution after intermolecularcyclization. However, if the above A is a radical (iii) or (iv), a finalproduct having an ether or amide linkage is relatively stabilized, it ispossible to perform the substitution prior to intermolecularcyclization. The above matter is explained in more detail as illustratedin the following reaction scheme 2.

[0034] (wherein, A′ is a radical (iii) or (iv) as defined above; R₁ isthe same as defined above; L is bromine or mesylate).

[0035] From the above reaction scheme 2, the first step is a reaction inwhich radical A′ is substituted; the structural 12, a starting material,is reacted with A′H in the presence of sodium hydride and base to obtainthe compound 13. The compound 12 is used as a starting material wherethe leaving group is attached to its terminal group so as to facilitatethe substitution ; if the leaving group is mesylate, the compound 12 maybe obtained by the reaction of 1,6hexanediol with methanesulfonylchloride.

[0036] As illustrated in the reaction scheme 1, the compound 13, soformed, is reacted with dimalonate and followed by the intramolecularcyclization, oxirane carboxylic acid derivative of the formula 1 may beobtained as a final product.

[0037] The compound of the formula 1 according to this invention may beused as an effective antidiabetic agent. The daily effective dose inadult is 10-100 mg/kg.

[0038] The compound of the formula 1 according to this invention hasproven to have remarkable blood glucose lowering effects, while beingsafe in LD₅₀.

[0039] According to this invention, an antidiabetic agent containing thecompound of the formula 1 as an active ingredient may be administeredvia the following common dosage forms, i.e., tablets, injections,capsules, etc.

[0040] This invention relates to a novel oxirane carboxylic acidderivative and its manufacturing method. Based on its inhibitorymechanism on the CPT I, oxirane carboxylic acid derivative of thisinvention has blood glucose lowering effects so that the abovederivative may be effectively used as an antidiabetic agent havingremarkable antidiabetic activity and less side effects.

BEST MODE FOR CARRYING OUT THE INVENTION

[0041] This invention is explained in more detail by the followingexamples, but the claims are not limited to these examples.

EXAMPLE 1 Ethyl-2-[6-(4chlorophenylcarboxyl)hexyl]-oxirane-2-carboxylicacid

[0042] 1) In a 500 ml round-bottomed flask, 60% sodium hydride (6.84 g,170.92 mmol) was placed, and the air inside the flask was substituted byargon gas. Dry tetrahydrofuran (200 ml) was added dropwise thereto toform a suspension. After cooling the mixture to 0° C., a solution of1,6-hexanediol (20 g, 169.23 mmol) in dry tetrahydrofuran (200 ml) wasslowly added dropwise, and the mixture stirred at room temperature for20 minutes. Benzyl bromide (20.25 ml, 170.25 mmol) was added dropwisethereto stirred at room temperature for 18 hrs and the reaction mixturewas concentrated under reduced pressure to remove tetrahydrofuran as asolvent The residue was diluted with a mixture of ethyl acetate (400 ml)and water (50 ml). After washing with water (500 ml×2) and saturatedbrine (500 ml×2), the solution was dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified on a column chromatography (eluent: ethylacetate/n-hexane=⅓) to give 19.47 g of object compound as colorless oil(yield: 55%).

[0043] IR(neat) 3400(alcohol) cm⁻¹

[0044] Mass(EI) 208(M⁺−1)

[0045]¹H—NMR (80 MHz, CDCl₃) δ

[0046] 7.43(s, 5H), 4.53(s,2H), 3.66(t, 2H), 3.50(t, 2H), 1.81-1.20(m,8H)

[0047] 2) In a 250 ml round-bottomed flask, 6-benzyloxy-1-hexanol (14.2g, 67.87 mmol) and p-toluenesulfonyl chloride (14.23 g, 74.66 mmol) wereplaced, and the air inside the flask was substituted by argon gas. Drychloroform (120 ml) was added dropwise thereto, and then dry pyridine(16.47 ml) was injected to the mixture. After stirring at roomtemperature for 3 hours, the reaction mixture was concentrated underreduced pressure to remove chloroform, and the residue was diluted withethyl acetate (400 ml). The solution was washed with diluted aqueoushydrochloric acid (20 ml×2), water (30 ml×2) and saturated brine (30ml×2), dried over anhydrous magnesium sulfate and filtered. Afterconcentrating the solution under reduced pressure, the residue waspurified on a column chromatography (eluent: ethylacetate/n-hexane={fraction (1/10)}) to obtain 24 g of the objectcompound as colorless oil (yield: 97%).

[0048] Mass(EI) 362(M⁺−1) ¹H—NMR (400 MHz, CDCl₃) δ

[0049] 7.63(d, 2H), 7.15(s, 7H), 4.33(s, 2H), 3.86(t, 2H), 3.27(t, 2H),2.29(s, 3H), 1.52-1.11(m, 8H)

[0050] 3) Diethyl malonate (1.85 ml, 12.19 mmol, 1.1 eq.) was dissolvedin dry tetrahydrofuran (25 ml), and the solution chilled to 0° C. Sodiumhydroxide (95%) (308 mg, 12.19 mmol, 1.1 eq.) was added thereto, and theresultant mixture stirred about 10 minutes at the same temperature. Tothe mixture, a solution of 6-benzoxy-1-(4-methylbenzenesulfoxy)hexane(3.24 g, 11.08 mmol) in tetrahydrofuran (20 ml) was slowly addeddropwise, and the mixture stirred for a while. After heating underreflux for 16 hours, the mixture was concentrated under reduced pressureto remove tetrahydrofuran. The residue was diluted with ethyl acetate(150 ml) and the solution washed with distilled water (120 ml), 1Naqueous hydrochloric acid (120 ml×2), 5% sodium bicarbonate (120 ml×2)and saturated brine (80 ml). Then the solution was dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The obtained residue was purified on a column chromatography (ethylacetate/n-hexane=⅕) to give diethyl 6-benzoxyhexylmalonate (3.5 g,88.6%) as pale yellow clear oil.

[0051]¹H—NMR (300 MHz, CDCl₃) δ

[0052] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.65(s, 2H), 4.2(q, 4H), 3.46(t,2H), 3.3(t, 1H), 1.9(m, 2H), 1.6(m, 2H), 1.32(m, 6H), 1.27(t, 6H)

[0053] 4) Diethyl 6-benzoxyhexylmalonate (3.5 g, 9.82 ml) was dissolvedin absolute ethanol (30 ml), and potassium hydroxide (85%) (694 mg,10.51 mmol, 1.07 eq.) was added thereto. After stirring about 4-5 hoursat ambient temperature, the reaction mixture was concentrated underreduced pressure to remove ethanol. The residue was diluted withdistilled water (150 ml), and the organic impurities were washed byusing ethyl acetate. The water layer was acidified with 1N aqueoushydrochloric acid to pH 2-3, extracted with ethyl acetate (50 ml×3), andwashed with 1N aqueous hydrochloric acid (100 ml) and saturated brine(80 ml). The extract was dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give ethyl6-benzoxyhexyl malonate (2.42 g, 75%) as pale yellow clear oil.

[0054]¹H—NMR (300 MHz, CDCl₃) δ

[0055] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.66(sd, 2H), 4.22(q, 2H), 3.46(t,2H), 3.36(t, 1H), 1.9(m, 2H), 1.6(m, 2H), 1.34(m, 6H), 1.28(t, 3H)

[0056] 5) Dissolved was ethyl 6-benzoxyhexylmalonate (2.42 g, 7.37 ml)in dry tetrahydrofuran (70 ml), and sodium hydride (335 mg, 13.27 mmol,1.8 eq.) was added thereto at 0° C. The mixture was stirred at roomtemperature for 20 to 30 minutes. When sodium hydride was practicallydissolved, Eschenmoser salt (1.64 g, 8.84 mmol, 1.2 eq.) was added insolid state. After stirring for a while, the mixture was heated underreflux for 16 hours. The reaction mixture was concentrated under reducedpressure to remove tetrahydrofuran, and the residue was diluted withethyl acetate (150 ml), and washed with distilled water (120 ml), 1Naqueous hydrochloric acid (120 ml×2), 5% sodium bicarbonate (120 ml×2)and saturated brine (80 ml). The solution was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on a column chromatography (ethyl acetate/n-hexane={fraction (1/10)}) to obtain ethyl 2-(6-benzoxy)hexyl-2-enepropionate(1.82 g, 83%) as pale yellow clear oil.

[0057]¹H—NMR (300 MHz, CDCl₃) δ

[0058] 7.28(q, 1H), 7.0-6.95(m, 2H), 6.12(d, 1H), 5.50(d, 1H), 4.65(sd,2H), 4.20(q, 2H), 3.47(t, 2H), 2.29(m, 2H), 1.60(m, 2H), 1.45(m, 2H),1.35(m, 4H), 1.30(t, 3H)

[0059] 6) To a mixture of distilled water (32 ml), NMO (60 wt %) (1.17ml, 6.75 mmol, 1.1 eq.) and acetone (28 ml), a solution of 2.5% osmiumtetroxide in t-butanol (0.1 M) (3.07 ml, 0.307 mmol, 0.05 eq.) andt-butanol (10 ml) were added and the mixture stirred. The mixture wasadded to ethyl 2-(6-benzoxy)hexyl-2-enepropionate (1.82 g, 6.14 mmol),and the resultant mixture stirred at room temperature for 1.5 hours. Tothe mixture, Na₂S₂O₄ (about 2 g) was added to quench the reaction, andthe reaction mixture was concentrated under reduced pressure to removeacetone. The residue was diluted with ethyl acetate (150 ml), and thesolution washed with distilled water (120 ml×3) and saturated brine (80ml), and then dried over anhydrous magnesium sulfate. The residue afterfiltering and concentrating the solution under reduced pressure waspurified on a column chromatography (eluent: ethyl acetate/n-hexane=½)to quantitatively obtain ethyl2,3-dihydroxy-2-(6-benzoxy)hexylpropionate (2.02 g) as colorless clearoil.

[0060]¹H—NMR (300 MHz, CDCl₃) δ

[0061] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.65(s, 2H), 4.27(dq-dq, 2H), 3.78(t, 1H), 3.58(dd, 1H), 3.55(s, 1H), 3.46(t, 2H), 2.19(dd, 1H),1.7-1.5(m, 3H), 1.4-1.0(m, 5H, t, 3H)

[0062] 7) Ethyl 2,3-dihydroxy-2-(6-benzoxy)hexylpropionate (2.02 g, 6.11mmol) was properly dissolved in pyridine (30 ml), and p-toluenesulfonylchloride (11.65 g, 61.1 mmol, 10 eq.) was added thereto. After stirringabout 3 hours, the reaction mixture was diluted by adding ethyl acetate(150 ml). The solution was washed with IN aqueous hydrochloric acid (120ml×3), 5% sodium bicarbonate (120 ml×2), distilled water (120 ml) andsaturated brine (80 ml), and then dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified on a column chromatography (eluent: ethylacetate/n-hexane=⅕) to give ethyl2-hydroxy-3-(4-methylbenzenesulfoxy)-2-[6-benzoxyhexyl]propionate (2.56g, 86.5%) as white solid.

[0063]¹H—NMR (300 MHz, CDCl₃) δ

[0064] 7.77(d, 2H), 7.34(d, 2H), 7.28(s, 1H), 6.97(s, br, 2H), 4.63(s,2H), 4.22(m, 3H), 3.08(d, 1H), 3.43(t, 2H), 3.35(s, 1H), 2.45(s, 3H),1.7-1.4(m, 4H), 1.4-1.15(m, 5H, t, 3H), 1.1(m, 1H)

[0065] 8) In a 50 ml round-bottomed flask, ethyl2-hydroxy-3-(4-methylbenzenesulfoxy)2-[6-benzoxyhexyl]propionate (250mg, 0.52 mmol) and anhydrous potassium carbonate (71.86 mg, 0.52 mmol)were placed, and absolute ethanol (10 ml) was injected thereto. Themixture was stirred at room temperature for 5 hours, and concentratedunder reduced pressure. The residue was purified on a columnchromatography (eluent: ethyl acetate/n-hexane=½) to obtain the objectcompound (160 mg) as colorless oil (yield: 98%).

[0066] Mass(EI) 306(M⁺)

[0067] IR 1740(ester carbonyl)

[0068]¹H—NMR (500 MHz, CDCl₃) δ

[0069] 7.33(s, 5H), 4.48(s, 2H), 4.22-4.20(m, 2H), 3.44(t, 2H), 3.01(d,1H), 2.75(d, 1H), 1.54-1.29(m, 10H), 1.26(t, 3H)

[0070] 9) In a Parr bottle, ethyl 2-[6-benzoxyhexyl]-2-oxiranecarboxylate (528 mg, 1.725 mmol) and catalytic amount of 10% Pd/C wereplaced, and absolute ethanol was injected thereto. The mixture wasstirred at room temperature for 5 hours under 40-50 psi hydrogen stream.The reaction mixture was filtered under reduced pressure andconcentrated under reduced pressure, and the residue purified on acolumn chromatography (eluent: ethyl acetate/n-hexane) to obtain 360 mgof object compound as colorless oil (yield: 96%).

[0071] Mass(EI) 218(M⁺+2)

[0072] IR 1740(ester carbonyl) 3400(alcohol)

[0073]¹H—NMR (500 MHz, CDCl₃) δ

[0074] 4.23-4.20(m, 2H), 3.63(t, 2H), 3.01(d, 1H), 2.76(d, 1H),1.58-1.36(m, 10H), 1.28(t, 3H)

[0075] 10) In a 25 ml round-bottomed flask,ethyl-6-hydroxyhexyloxirane-2-carboxylic acid (173 mg, 0.80 mmol),4-chlorobenzoylcarboxylic acid (137 mg, 0.88 mmol),dicyclohexylcarbodiimide (181.57 mg, 0.88 mmol) anddimethylaminopyridine (9.77 mg, 0.80 mmol) were placed, and the airinside the flask was substituted by argon gas. After injecting drymethylene chloride (5 ml) thereto, the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was filtered under reducedpressure and concentrated under reduced pressure, and the residuepurified on a column chromatography (eluent: ethylacetate/n-hexane={fraction (1/10)}) to obtain 280 mg of the objectcompound as colorless oil (yield: 98%).

[0076] MASS(EI) 354(M⁺)

[0077] IR 1740(ester carbonyl)

[0078]¹H—NMR(500 MHz, CDCl₃) δ

[0079] 7.79(d, 2H), 7.41(d, 2H), 4.30(t, 2H), 4.23-4.18(m, 2H), 3.02(d,1H), 2.78(d, 1H), 1.77-1.29(m, 10H), 1.28(t, 3H)

EXAMPLE 2Ethyl-2-[6-(5-methyl-2-pyrazincarboxyl)hexyl]-oxirane2-carboxylic acid

[0080] The procedures described in Example 1-1)˜1-10) were repeated butusing 5-methyl-2-pyrazincarboxylic acid instead of4-chlorobenzoylcarboxylic acid of Example 1-10) to obtain the titlecompound.

[0081] IR(neat) 1740(ester carbonyl)

[0082] MASS(EI) 337(M⁺+1)

[0083]¹H NMR(500 MHz, CDCl₃) δ

[0084] 9.16(d, 1H), 8.57(d, 1H), 4.42(t, 2H), 4.22-4.20(m, 2H), 3.01(d,1H), 2.75(d, 1H), 2.66(s, 3H), 1.83-1.33(m, 10H), 1.28(t, 3H)

EXAMPLE 3Ethyl-2-[6-(5-bromo-3-pyridincarboxyl)hexyl]-oxirane-2-carboxylic acid

[0085] The procedures described in Example 1-1)˜1-10) were repeated butusing 5-bromo3-pyridincarboxylic acid instead of4-chlorobenzoylcarboxylic acid of Example 1-10) to obtain the titlecompound.

[0086] IR(neat) 1740(ester carbonyl)

[0087] MASS(EI) 400(M⁺)

[0088]¹H NMR(500 MHz, CDCl₃) δ

[0089] 9.11(s, 1H), 8.83(s, 1H), 8.41(s, 1H), 4.35(t, 2H), 4.23-4.20(m,2H), 3.02(d, 1IH), 2.76(d, 1H, 1.79-1.41(m, 10H), 1.28(t, 3H)

EXAMPLE 4Ethyl-2-[6-(2,6dimethoxy-5-pyridincarboxyl)hexyl]-oxirane-2-carboxylicacid

[0090] The procedures described in Example 1-1)˜1-10) were repeated butusing 2,6dimethoxy-5-pyridincarboxylic acid instead of 4-chlorobenzoylcarboxylic acid of Example 1-10) to obtain the title compound.

[0091] IR(neat) 1740(ester carbonyl)

[0092] MAS(EI) 381(M⁺)

[0093]¹H NMR(500 MHz, CDCl₃) δ

[0094] 8.11(d, 1H), 6.31(d, 1H), 4.24(t, 2H), 4.23-4.21(m, 2H),4.03(s,3H), 3.96(s, 3H), 3.01(d, 1H), 2.76(d, 1H), 1.74-1.39(m, 10H), 1.28(t,3H)

EXAMPLE 5 Ethyl-2-[6(2-thiophenecarboxyl)hexyl]-oxirane-2-carboxylicacid

[0095] The procedures described in Example 1-1)˜1-10) were repeated butusing 2-thiophenecarboxylic acid instead of 4-chlorobenzoylcarboxylicacid of Example 1-10) to obtain the title compound.

[0096] IR(neat) 1740(ester carbonyl)

[0097] MASS(EI) 326(M⁺)

[0098]¹H NMR(500 MHz, CDCl₃) δ

[0099] 7.79(d, 1H), 7.54(d, 1H), 7.12-7.08(M, 1H), 4.28(t,2H),4.23-4.19(M, 2H), 3.01(d, 1H), 2.76(d, 1H), 1.76-1.40(m, 10H),1.28(t, 3H)

[0100]¹³C NMR (75 MHz, CDCl₃) δ

[0101] 170.35, 162.26, 134.0, 133.21, 132.15, 127.66, 65.07, 61.54,56.93, 51.79, 31.11, 29.08, 28.50, 25.71, 24.63, 14.08

EXAMPLE 6 Ethyl-2-[6-(2-pyrazincarboxyl)hexyl]-oxirane-2-carboxylic acid

[0102] The procedures described in Example 1-1)˜1-10) were repeated butusing 2-pyrazincarboxylic acid instead of 4-chlorobenzoylcarboxylic acidof Example 1-10) to obtain the title compound.

[0103] IR(neat) 1740(ester carbonyl)

[0104] MASS(EI) 322(M⁺)

[0105]¹H NMR(500 MHz, CDCl₃) δ

[0106] 9.30(s, 1H), 8.78(d, 1H), 8.75(d, 1H), 4.44(t, 2H), 4.22-4.21(m,2H), 3.01(d, 1H), 2.76(d, 1H), 1.84-1.41(m, 10H), 1.28(t, 3H)

EXAMPLE 7 Ethyl-2-[6-(2-thiopheneacetyl)hexyl]-oxirane-2-carboxylic acid

[0107] The procedures described in Example 1-1)˜1-10) were repeated butusing 2-thiopheneacetylic acid instead of 4-chlorobenzoylcarboxylic acidof Example 1-10) to obtain the title compound.

[0108]¹H NMR (300 MHz, CDCl₃) δ

[0109] 7.22 (1H, dd, J=4.81 Hz, J=1.44 Hz, thiophene H₅), 6.96 (2H, m,thiophene H₃, H₄), 4.22 (2H, m, CO₂CH₂CH₃), 4.11 (2H, t, J=6.63 Hz,CO₂CH₂—), 3.83 (2H, s, Ar—CH₂CO₂—), 3.03 (1H, d, J=5.88 Hz, 1H ofoxirane), 2.77 (1H, d, J=5.91 Hz, 1H of oxirane), 2.08 (1H, m, aliphaticH), 1.64 (3H, m, aliphatic H), 1.45˜1.35 (6H, m, aliphatic H), 1.29 (3H,t, J=7.12 Hz, CO₂CH₂CH₃)

[0110]¹³C NMR (75 MHz, CDCl₃) δ

[0111] 170.48, 170.36, 135.17, 126.72 (2 C's), 124.96, 65.14, 61.54,56.93, 51.79, 35.50, 31.09, 29.02, 28.33, 25.59, 24.59, 14.08

EXAMPLE 8 Ethyl-2-[6-(3-thiophenecarboxyl)hexyl]-oxirane-2-carboxylicacid

[0112] The procedures described in Example 1-1)˜1-10) were repeated butusing 3-thiophenecarboxylic acid instead of 4-chlorobenzoylcarboxylicacid of Example 1-10) to obtain the title compound.

[0113]¹H NMR (300 MHz, CDCl₃) δ

[0114] 8.10 (1H, dd, J=2.9 Hz, J=0.8 Hz, thiophene H₂), 7.53 (1H, dd,J=5.0 Hz, J=0.71 Hz, thiophene H₄), 7.31 (1H, dd, J=5.06 Hz, is J=3.07Hz, thiophene H₅), 4.24 (4H, m, CO₂CH₂CH₃, CO₂CH₂—), 3.03 (1H, d, J=5.91Hz, 1H of oxirane), 2.78 (1H, d, J=5.87 Hz, 1H of oxirane), 2.11 (1H, m,aliphatic H), 1.70 (3H, m, aliphatic H), 1.45 (6H, m, aliphatic H), 1.29(3H, t, J=7.14 Hz, CO₂CH₂CH₃)

[0115]¹³C NMR (75 MHz, CDCl₃) δ

[0116] 170.41, 162.87, 133.90, 132.52, 127.90, 125.95, 64.67, 61.60,56.98, 51.86, 31.16, 29.15, 28.58, 25.82, 24.68, 14.12

EXAMPLE 9 Ethyl-2-[6-(3-thiopheneacetyl)hexyl]-oxirane2-carboxylic acid

[0117] The procedures described in Example 1-1)˜1-10) were repeated butusing 3-thiopheneacetylic acid instead of 4-chlorobenzoylcarboxylic acidof Example 1-10) to obtain the title compound.

[0118]¹H NMR (300 MHz, CDCl₃) δ

[0119] 7.29 (1H, dd, J=4.87 Hz, J=3.02 Hz, thiophene H₅), 7.15 (1H, m,thiophene H₂), 7.04 (1H, dd, J=4.87 Hz, J=0.71 Hz, thiophene H₄), 4.23(2H, m, CO₂CH₂CH₃), 4.09 (2H, t, J=6.64 Hz, CO₂CH₂—), 3.65 (2H, s,Ar—CH₂CO₂—), 3.03 (1H, d, J=5.87 Hz, 1H of oxirane), 2.78 (1H, d, J=5.87Hz, 1H of oxirane), 2.09 (1H, m, aliphatic H), 1.68˜1.27 (9H, m,aliphatic H), 1.29 (3H, t, J=7.15 Hz, CO₂CH2CH₃)

[0120]¹³C NMR (75 MHz, CDCl₃) δ

[0121] 171.20, 170.39, 133.70, 128.46, 125.66, 122.77, 64.89, 61.59,56.96, 51.84, 35.92, 31.11, 29.05, 28.38, 25.63, 24.62, 14.11

EXAMPLE 10Ethyl-2-[6-(5-nitro-2-furancarboxyl)hexyl]-oxirane2-carboxylic acid

[0122] The procedures described in Example 1-1)˜1-10) were repeated butusing 5-nitro-2-furancarboxylic acid instead of4-chlorobenzoylcarboxylic acid of Example 1-10) to obtain the titlecompound.

[0123]¹H NMR (300 MHz, CDCl₃) δ

[0124] 7.36 (1H, d, J=3.65 Hz, furan H), 7.39 (1H, d, J=3.69 Hz, furanH), 4.37 (2H, t, J=6.52 Hz, CO₂CH—), 4.22 (2H, m, CO₂CH₂CH₃), 3.04 (1H,d, J=5.76 Hz, 1H of oxirane), 2.79 (1H, d, J=5.77 Hz, 1H of oxirane),2.11 (1H, m, aliphatic H), 1.67 (3H, m, aliphatic H), 1.43 (6H, m,aliphatic H), 1.29 (3H, t, J=7.06 Hz, CO₂CH₂CH₃)

[0125]¹³C NMR (75 MHz, CDCl₃) δ

[0126] 170.34 (2 C's), 157.02, 144.98, 118.66, 111.48, 66.26, 61.57,56.90, 51.81, 31.07, 28.98, 28.29, 25.56, 24.58, 14.07

EXAMPLE 11 Ethyl-2-[6(2-thiophenemethoxy)hexyl]-oxirane-2-carboxylicacid

[0127] 1) Dissolved was 1,6-hexanediol (5 g, 42.31 mmol) in dryltetrahydrofuran (70 ml), and methanesulfonyl chloride (7.2 ml, 93.08mmol, 2.2 eq.) and triethylamine (14.74 ml, 105.78 mmol, 2.5 eq.) wereinjected thereto at 0° C. After stirring at 0° C. for about 1.5 hours,the reaction mixture was diluted by adding dichloromethane (250 ml), andthe solution washed with distilled water (200 ml×2), 1N aqueoushydrochloric acid (200 ml×2), 5% aqueous sodium bicarbonate solution(200 ml×2) and saturated brine (100 ml). The solution was then driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was recrystallized from ethylacetate/n-hexane to give 1,6-hexylmesylate (10.67 g, 91.9%) as whiteneedle crystal.

[0128]¹H—NMR (300 MHz, CDCl₃) δ

[0129] 4.24(t, 4H), 3.02(s, 6H), 1.8(m, 4H), 1.5(m, 4H)

[0130] 2) Dissolved was 2-thiophenemethanol (2.0 g, 17.52 mmol) intetrahydrofuran (100 ml), and sodium hydride (95%) (442 mg, 17.52 mmol,1.0 eq.) was added thereto at 0° C. After stirring the mixture at thesame temperature for 10 minutes, 1,6-dimethanesulfoxyhexane (5.77 g,21.02 mmol, 1.2 eq.) was added thereto, and the resultant mixturestirred for 16 hours. The reaction mixture was concentrated underreduced pressure to remove tetrahydrofuran, and the residue was dilutedwith ethyl acetate (200 ml). The solution was washed with distilledwater (180 ml), 1N aqueous hydrochloric acid (180 ml×2), 5% sodiumbicarbonate (180 ml×2) and saturated brine (100 ml), and then dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified on a column chromatography (ethylacetate/n-hexane=⅕) to give6-methanesulfoxy-1-(2-thiophenemethoxy)hexane (3.24 g, 63.2%) as paleyellow oil.

[0131]¹H—NMR (300 MHz, CDCl₃) δ

[0132] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.66(sd, 2H), 4.22(t, 2H), 3.48(t,2H), 2.99 (s, 3H), 1.75(m, 2H), 1.6(m, 2H), 1.4(m, 4H)

[0133] 3) Diethyl malonate (1.85 ml, 12.19 mmol, 1.1 eq.) was dissolvedin dry tetrahydrofuran (25 ml), and the solution chilled to 0° C. Sodiumhydride (95%) (308 mg, 12.19 mmol, 1.1 eq.) was added thereto, and theresultant mixture stirred about 10 minutes at the same temperature. Tothe mixture, a solution of 6-methanesulfoxy-1-(2-thiophenemethoxy)hexane(3.24 g, 11.08 mmol) in tetrahydrofuran (20 ml) was slowly addeddropwise, and the mixture stirred for a while. After heating underreflux for 16 hours, the mixture was concentrated under reduced pressureto remove tetrahydrofuran. The residue was diluted with ethyl acetate(150 ml) and the solution washed with distilled water (120 ml), 1Naqueous hydrochloric acid (120 ml×2), 5% sodium bicarbonate (120 ml×2)and saturated brine (80 ml). Then the solution was dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The obtained residue was purified on a column chromatography (ethylacetate/n-hexane=⅕) to give diethyl 6-(2-thiophenemethoxy)hexylmalonate(3.5 g, 88.6%) as pale yellow clear oil.

[0134]¹H—NMR (300 MHz, CDCl₃) δ

[0135] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.65(s, 2H), 4.2(q, 4H), 3.46(t,2H), 3.3(t, 1H), 1.9(m, 2H), 1.6(m, 2H), 1.32(m, 6H), 1.27(t, 6H)

[0136] 4) Diethyl 6-(2-thiophenemethoxy)hexylmalonate (3.5 g, 9.82 ml)was dissolved in absolute ethanol (30 ml), and potassium hydroxide (85%)(694 mg, 10.51 mmol, 1.07 eq.) was added thereto. After stirring about4-5 hours at ambient temperature, the reaction mixture was concentratedunder reduced pressure to remove ethanol. The residue was diluted withdistilled water (150 ml), and the organic impurities were washed byusing ethyl acetate. The water layer was acidified with 1N aqueoushydrochloric acid to pH 2-3, extracted with ethyl acetate (50 ml×3), andwashed with 1N aqueous hydrochloric acid (100 ml) and saturated brine(80 ml). The extract was dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to give ethyl6-(2-thiophenemethoxy)hexyl malonate (2.42 g, 75%) as pale yellow clearoil.

[0137]¹H—NMR (300 MS, CDCl₃) δ

[0138] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.66(sd, 2H), 4.22(q, 2H), 3.46(t,2H), 3.36(t, 1H), 1.9(m, 2H), 1.6(m, 2H), 1.34(m, 6H), 1.28(t, 3H)

[0139] 5) Dissolved was ethyl 6-(2-thiophenemethoxy)hexylmalonate (2.42g, 7.37 ml) in dry tetrahydrofuran (70 ml), and sodium hydride (335 mg,13.27 mmol, 1.8 eq.) was added thereto at 0° C. The mixture was stirredat room temperature for 20 to 30 minutes. When sodium hydride waspractically dissolved, Eschenmoser salt (1.64 g, 8.84 mmol, 1.2 eq.) wasadded in solid state. After stirring for a while, the mixture was heatedunder reflux for 16 hours. The reaction mixture was concentrated underreduced pressure to remove tetrahydrofuran, and the residue was dilutedwith ethyl acetate (150 ml), and washed with distilled water (120 ml),1N aqueous hydrochloric acid (120 ml×2), 5% sodium bicarbonate (120 ml×2) and saturated brine (80 ml). The solution was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on a column chromatography (ethyl acetate/n-hexane={fraction (1/10)}) to obtain ethyl2-[6-(2-thiophenemethoxy)hexyl-2-enepropionate] (1.82 g, 83%) as paleyellow clear oil.

[0140]¹H—NMR (300 MHz, CDCl₃) δ

[0141] 7.28(q, 1H), 7.0-6.95(m, 2H), 6.12(d, 1H), 5.50(d, 1H), 4.65(sd,2H), 4.20(q, 2H), 3.47(t, 2H), 2.29(m, 2H), 1.60(m, 2H), 1.45(m, 2H),1.35(m, 4H), 1.30(t, 3H)

[0142] 6) To a mixture of distilled water (32 ml), NMO (60 wt %) (1.17ml, 6.75 mmol, 1.1 eq.) and acetone (28 ml), a solution of 2.5% osmiumtetroxide in t-butanol (0.1 M) (3.07 ml, 0.307 mmol, 0.05 eq.), andt-butanol (10 ml) were added and the mixture stirred. The mixture wasadded to ethyl 2-[6-(2-thiophenemethoxy)hexyl-2-enepropionate (1.82 g,6.14 mmol), and the resultant mixture stirred at room temperature for1.5 hours. To the mixture, Na₂S₂O₄ (about 2 g) was added to quench thereaction, and the reaction mixture was concentrated under reducedpressure to remove acetone. The residue was diluted with ethyl acetate(150 ml), and the solution washed with distilled water (120 ml×3) andsaturated brine (80 ml), and then dried over anhydrous magnesiumsulfate. The residue after filtering and concentrating the solutionunder reduced pressure was purified on a column chromatography (eluent:ethyl acetate/n-hexane=½) to quantitatively obtain ethyl2,3-dihydroxy-2-[6-(2-thiophenemethoxy)hexylpropionate (2.02 g) ascolorless clear oil.

[0143]¹H—NMR (300 MHz, CDCl₃) δ

[0144] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.65(s, 2H), 4.27(dq-dq, 2H),3.78(t, 1H), 3.58(dd, 1H), 3.55(s, 1H), 3.46(t, 2H), 2.19(dd, 1H),1.7-1.5(m, 3H), 1.4-1.0(m, 5H, t, 3H)

[0145] 7) Ethyl 2,3-dihydroxy-2-[6-(2-thiophenemethoxy)hexylpropionate(2.02 g, 6.11 mmol) was properly dissolved in pyridine (30 ml), andp-toluenesulfonyl chloride (11.65 g, 61.1 mmol, 10 eq.) was addedthereto. After stirring about 3 hours, the reaction mixture was dilutedby adding ethyl acetate (150 ml). The solution was washed with 1Naqueous hydrochloric acid (120 ml×3), 5% sodium bicarbonate (120 ml×2),distilled water (120 ml) and saturated brine (80 ml), and then driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified on a column chromatography(eluent: ethyl acetate/n-hexane=⅕) to give ethyl2-hydroxy-3-[4-methoxybenzenesulfoxy)-2-[6-(2-thiophenemethoxy)hexyl]propionate(2.56 g, 86.5%) as white solid.

[0146]¹H—NMR (300 MHz, CDCl₃) δ

[0147] 7.77(d, 2H), 7.34(d, 2H), 7.28(s, 1H), 6.97(s, br, 2H), 4.63,(s,2H), 4.22(m, 3H), 3.08(d, 1H), 3.43(t, 2H), 3.35(s, 1H), 2.45(s, 3H),1.7-1.4(m, 4H), 1.4-1.15(m, 5H, t, 3H), 1.1(m, 1H)

[0148] 8) The compound obtained above (2.56 g, 5.28 mmol) was dissolvedin absolute ethanol (100 ml), and potassium carbonate (7.3 g, 52.8 mmol,10 eq.) was added thereto. After stirring at room temperature for 6hours, the reaction mixture was filtered to remove excess potassiumcarbonate, and the filtrate concentrated under reduced pressure toremove ethanol. The residue was diluted with ethyl acetate (150 ml), andthe solution washed with distilled water (120 ml×2), 5% aqueous citricacid (120 ml×2) and saturated brine (100 ml), and dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on a column chromatography (eluent: ethylacetate/n-hexane =⅕) to giveethyl-2-[6-(2-thiophenemethoxy)hexyl]-oxirane-2-carboxylic acid (1.41 g,85.5%) as colorless clear oil.

[0149]¹H—NMR (300 MHz, CDCl₃) δ

[0150] 7.28(q, 1H), 7.0-6.95(m, 2H), 4.65(s, 2H), 4.22(dq-dq, 2H),3.46(t, 2H), 3.02(d, 1H), 2.78(d, 1H), 2.08(m, 1H), 1.6(m, 3H),1.5-1.3(m, 6H), 1.29(t, 3H)

[0151]¹³C—NMR (75 MHz, CDCl₃) δ

[0152] 170.45, 141.45, 126.58, 126.15, 125.63, 70.0, 67.31, 61.59,57.04, 51.84, 31.17, 29.50, 29.32, 25.93, 24.72, 14.13

EXAMPLE 12 Ethyl-2-[6-(3,5-dimethylpyrazole)hexyl]oxirane-2-carboxylicacid

[0153] In a 100 ml round-bottomed flask, 60% sodium hydride (158.4 mg,3.96 mmol) was placed, and the air inside the flask was substituted byargon gas. Dry tetrahydrofuran (5 ml) was added dropwise thereto to forma suspension. After chilling the mixture to 0° C., a solution of3,5-dimethylpyrazole-1-methanol (500 mg, 3.96 mmol) in drytetrahydrofuran (3 ml) was added dropwise, and then 1,6-dibromohexane(0.55 ml, 3.6 mmol) was slowly added dropwise thereto. After heatingunder reflux for 16 hours, the reaction mixture was concentrated underreduced pressure, and the residue was diluted with a mixture of ethylacetate (150 ml) and water (10 ml). After washing with water (5 ml×2)and saturated brine (5 ml×2), the solution was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified on a column chromatography (eluent: ethylacetate/n-hexane=⅓) to give 340 mg of6-(3,5-dimethylpyrazole)-1-bromohexanol as colorless oil (yield: 33%).

[0154] Mass(EI) 260(M+)

[0155]¹H NMR (80M, CDCl₃) δ

[0156] 5.80(s, 1H), 3.98(t, 2H), 3.38(t, 2H), 2.25(s, 6H), 1.92-1.42(m,8H)

[0157] After this, the procedures described in Example 11 were repeatedto give the final product,ethyl-2-[6-(3,5-dimethyl-pyrazol)hexyl]oxirane-2-carboxylic acid in ahigh yield.

EXAMPLE 13Ethyl-2-[6-(5-methoxy-2-thiophenemethoxy)hexyl]oxirane-2-carboxylic acid

[0158] The procedures described in Example 11-1)˜11-8) were repeated butusing 5-methoxy-2-thiophenemethanol instead of 2-thiophenemethanol ofExample 11-2) to obtain the title compound.

[0159]¹H NMR (300 MHz, CDCl₃)

[0160] 6.6(d, 1H), 6.03(d, 1H), 4.48(s, 2H), 4.21(dq-dq,2H), 3.87(s,3H), 3.42(t, 2H), 3.02(d, 1H), 2.77(d, 1H), 2.07(m, 1), 1.7-1.5(m, 3H),1.5-1.3(m, 6H), 1.29(t, 3H)

[0161]¹³C NMR (75 MHz, CDCl₃) δ

[0162] 170.4, 166.68, 127.40, 124.09, 102.83, 69.54, 68.01, 61.52,60.15, 56.99, 51.77, 31.14, 29.46, 29.29, 25.91, 24.68, 14.08

EXAMPLE 14Ethyl-2-[6-(5-methyl-2-thiophenemethoxy)hexyl]oxirane-2-carboxylic acid

[0163] The procedures described in Example 11-1)˜11-8) were repeated butusing 5-methyl-2-thiophenemethanol instead of 2-thiophenemethanol ofExample 11-2) to obtain the title compound.

[0164]¹H NMR (300 MHz, CDCl₃) δ

[0165] 6.76(d, 1H), 6.60(m,1H), 4.56(s, 2H), 4.22(dq-dq,2H), 3.44(t,2H), 3.02(d, 1H), 2.78(d, 1H), 2.46(sd, 3H), 2.08(m,1H),1.7-1.5(m, 3H),1.5-2.3(m, 6H), 1.29(t, 3H)

EXAMPLE 15Ethyl-2-16-(5-methyl-2-furanmethoxy)hexyl]oxirane-2-carboxylic acid

[0166] The procedures described in Example 11 -1)˜11-8) were repeatedbut using 5-methyl-2-furanmethanol instead of 2-thiophenemethanol ofExample 11-2) to obtain the title compound.

[0167]¹H NMR(300 MHz, CDCl₃) δ

[0168] 6.17(d, 1H), 5.90(d, 1H), 4.36(s, 2H), 4.21(dq-dq, 2H), 3.44(t,2H), 3.02(d, 1H), 2.77(d, 1H), 2.28(s, 3H), 2.07(m, 1H), 1.6(m,3H),1.5-1.3(m, 6H), 1.29(t, 3H)

[0169]¹³C NMR (75 MHz, CDCl₃) δ

[0170] 170.28, 152.31, 150.01, 109.90, 105.98, 69.93, 65.92, 64.68,61.41, 56.87, 51.67, 31.03, 29.32, 29.18, 25.77, 24.58, 15.11, 13.98,13.50

EXAMPLE 16 Ethyl-2-[6-(2-thiophenethoxy)hexyl]oxirane-2-carboxylic acid

[0171] The procedures described in Example 11-1)˜11-8) were repeated butusing 2-thiophenethanol instead of 2-thiophenemethanol of Example 11 -2)to obtain the title compound.

[0172]¹H NMR (300 MHz, CDCl₃) δ

[0173] 7.13(dd, 1H), 6.92(dd, 1H), 6.84(dd, 1H), 4.21(dq-dq, 2H),3.64(t, 2H), 3.44(t, 2H), 3.08(t, 2H), 3.02(d, 1H), 2.77(d,1H), 2.08(m,1H), 1.7-1.3(m, 9H), 1.29(t, 3H)

[0174]¹³C NMR (75 MHz, CDCl₃) δ

[0175] 170.31, 141.29, 126.49, 124.90, 123.46, 71.25, 70.83, 61.45,56.91, 51.71, 31.05, 30.36, 29.42, 29.21, 25.84, 24.62, 14.01

EXAMPLE 17Ethyl-2-16-(5-chloro-2-thiophenemethoxy)hexyl]oxirane-2-carboxylic acid

[0176] The procedures described in Example 11-1)˜11-8) were repeated butusing 5-chloro-2-thiophenemethanol instead of 2-thiophenemethanol ofExample 11-2) to obtain the title compound.

[0177]¹H NMR (300 MHz, CDCl₃) δ

[0178] 6.77(d, 1H), 6.74(d, 1H), 4.54(s, 2H), 4.22(dq-dq,2H),3.45(t,2H), 3.02(d, 1H), 2.77(d, 1H), 2.08(m, 1H), 1.7-1.5(m,3H),1.5-1.3(m, 6H), 1.29(t, 3H)

[0179]¹³C NMR (75M, CDCl₃) δ

[0180] 170.40, 140.48, 129.91, 125.52, 125.27, 70.07, 67.53, 61.54,56.99, 51.79, 31.14, 29.44, 29.27, 25.88, 24.68, 14.10

EXAMPLE 18Ethyl-2-[6-(3-chloro-2-thiophenemethoxy)hexyl]oxirane-2-carboxylic acid

[0181] The procedures described in Example 11-1)˜11-8) were repeated butusing 3-chloro2-thiophenemethanol instead of 2-thiophenemethanol ofExample 11-2) to obtain the title compound.

[0182]¹H NMR (300 MHz, CDCl₃) δ

[0183] 7.26(d, 1H), 6.89(d, 1H), 4.63(s, 2H), 4.22(dq-dq,2H), 3.49(t,2H), 3.02(d, 1H), 2.77(d, 1H), 2.08(m, 1H), 1.6(m, 3H), 1.5-1.4(m, 6H),1.29(t, 3H)

[0184]¹³C NMR (75 MHz, CDCl₃) δ

[0185] 170.39, 134.10, 127.46, 124.67, 123.41, 70.34, 64.80, 61.53,56.99, 51.77, 31.14, 29.41, 29.25, 25.85, 24.68, 14.09

EXAMPLE 19Ethyl-2-[6(4methoxy-2-thiophenemethoxy)hexyl]oxirane-2-carboxylic acid

[0186] The procedures described in Example 11-1)˜11-8) were repeated butusing 4-methoxy-2-thiophenemethanol instead of 2-thiophenemethanol ofExample 11-2) to obtain the title compound.

[0187]¹H NMR (300 MHz, CDCl₃) δ

[0188] 6.65 (1H, s, thiophene H), 6.17 (1H, s, thiophene H), 4.54 (2H,s, Ar—CH₂O—), 4.22 (2H, m, CO₂CH₂CH₃), 3.78 (3H, s, —OCH₃), 3.45 (2H, t,J=6.43 Hz, ArCH₂O—CH₂—), 3.02 (1H, d, J=5.84 Hz, 1H of oxirane), 2.77(1H, d, J=5.83 Hz, 1H of oxirane), 2.07 (1H, m, aliphatic H), 1.7˜1.57(3H, m, aliphatic H), 1.44˜1.31 (6H, m, aliphatic H), 1.29 (3H, t,J=7.13 Hz, CO₂CH₂CH₃)

[0189]¹³C NMR (75 MHz, CDCl₃) δ

[0190] 170.37, 157.54, 140.54, 118.25, 96.45, 70.03, 67.63, 61.50,57.09, 56.97, 51.74, 31.11, 29.43, 29.26, 25.85, 24.66, 14.06

EXAMPLE 20 Ethyl-2-[6-(3-thiophenemethoxy)hexyl]oxirane2-carboxylic acid

[0191] The procedures described in Example 11-1)˜11-8) were repeated butusing 3-thiophenemethanol instead of 2-thiophenemethanol of Example11-2) to obtain the title compound.

[0192]¹H NMR (300 MHz, CDCl₃) δ

[0193] 7.30 (1H, d, J=4.82 Hz, J=2.97 Hz, thiophene H₅), 7.20 (1H, sd,thiophene H₂), 7.07 (1H, d(br), J=4.39 Hz, thiophene H₄), 4.50 (2H, s,Ar—CH₂O—), 4.21 (2H, m, CO₂CH₂CH₃), 3.44 (2H, t, J=6.55 Hz,ArCH₂O—CH₂—). 3.02 (1H, d, J=5.91 Hz, 1H of oxirane), 2.77 (1H, d,J=5.88 Hz, 1H of oxirane), 2.06 (1H, m, aliphatic H), 1.6 (3H, m,aliphatic H), 1.36 (6H, m, aliphatic H), 1.29 (3H, t, J=7.13 Hz,CO₂CH₂CH₃)

[0194]¹³C NMR (75 MHz, CDCl₃) δ

[0195] 170.37, 139.74, 127.24, 125.81, 122.46, 70.19, 68.04, 61.50,56.96, 51.75, 31.11, 29.51, 29.27, 25.92, 24.66, 14.06

EXAMPLE 21 Ethyl-2-[6-(3thiophenethoxy)hexyl]oxirane-2-carboxylic acid

[0196] The procedures described in Example 11-1)˜11-8) were repeated butusing 3-thiophenethanol instead of 2-thiophenemethanol of Example 11-2)to obtain the title compound.

[0197]¹H NMR (300 MHz, CDCl₃) δ

[0198] 7.26 (1H, dd, J=4.89 Hz, J=2.99 Hz, thiophene H₅), 7.02 (1H, m,thiophene H₂), 6.98 (1H, dd, J=4.9 Hz, J=1.34 Hz, thiophene H₄), 4.22(2H, m, CO₂CH₂CH₃), 3.62 (2H, t, J=7.09 Hz, Ar—CH₂CH₂O—), 3.43 (2H, t,J=6.59 Hz, ArCH₂CH₂O—CH₂—), 3.03 (1H, d, J=5.87 Hz, 1H of oxirane), 2.91(2H, t, J=7.16 Hz, Ar—CH₂CH₂O—), 2.78 (1H, d, J=5.92 Hz, 1H of oxirane),2.1 (1H, m, aliphatic H), 1.7˜1.3 (9H, m, aliphatic H), 1.29 (3H, t,J=7.16 Hz, CO₂CH₂CH₃)

[0199]¹³C NMR (75 MHz, CDCl₃) δ

[0200] 170.34, 139.24, 128.39, 125.04, 120.91, 70.86, 70.80, 61.48,56.93, 51.73, 31.07, 30.63, 29.45, 29.23, 25.87, 24.62, 14.02

[0201] EXAMPLE 22

Ethyl-2-[6-(2-thiophenoxy)hexyl]oxirane-2-carboxylic acid

[0202] The procedures described in Example 11-1)˜11-8) were repeated butusing 2-thiophenone instead of 2-thiophenemethanol of Example 11-2) toobtain the title compound.

[0203]¹H NMR (300 MHz, CDCl₃) δ

[0204] 6.71 (1H, dd, J=3.76 Hz, J=5.75 Hz, thiophene H₄), 6.53 (1H, dd,J=5.77 Hz, J=1.45 Hz, thiophene H₅), 6.19 (1H, dd, J=3.75 Hz, J=1.44 Hz,thiophene H₃), 4.20 (2H, m, CO₂CH₂CH₃) 4.02 (2H, t, J=6.44 Hz,ArO—CH₂—), 3.03 (1H, d, J=5.86 Hz, 1H of oxirane), 2.78 (1H, d, J=5.91Hz, 1H of oxirane), 2.11 (1H, m, aliphatic H), 1.77 (3H, m, aliphaticH), 1.45 (6H, m, aliphatic H), 1.29 (3H, t, J=7.13 Hz, CO₂CH₂CH₃)

[0205]¹³C NMR (75 MHz, CDCl₃) δ

[0206] 170.39, 165.72, 124.65, 111.67, 104.50, 73.74, 61.58, 56.97,51.83, 31.12, 29.13, 28.99, 25.65, 24.65, 14.10

EXPERIMENTAL EXAMPLE 1 Blood Glucose Lowering Effects of the CompoundsPrepared by the Procedures of Example 1˜6, 11˜18

[0207] Two groups of male diabetes-induced Sprague-Dawley rats (each of4-5 rats weighing about 250 g) were used for this experiment. 45 mg/kgof streptozotocin (STZ) dissolved in 0.1M citrate buffer (pH 4.5, 0-4°C.) was injected to the tail vein of fasted rats for 1 day. After elapseof 7 days, their blood glucose concentration were measured and animalshaving the blood serum concentration of more than 350 mg/dl were used asdiabetes-induced rats for this experiment. The rats were intravenouslyadministered at a daily dose of 1 ml/kg, while the normal control groupreceived equal volume of 0.1M citrate buffer.

[0208] 7 days after being treated with streptozotocin, diabetes-inducedrats were orally administered at a dose of 50 mg/kg of the compoundsprepared by the procedures of Examples 1-6, 11˜18. Then, at timeintervals of 90 mins, 120 mins and 180 mins, their blood glucoseconcentrations were measured and the smallest values were taken. Thecompounds of Example 1-13 were dissolved in 30% ethanol until its finalconcentration became 2 ml/kg, while the control group was orallyreceived equal volume of 30% ethanol.

[0209] Significant difference between two groups was determined by ANOVAtest, together with a post hoc test using Newman-Keuls test.

[0210] The test results was shown in the following table 1. TABLE 1Blood glucose lowering effects of the Examples 1˜6, 11˜18 Compound Bloodglucose lowering rate % Example 1 11.8 Example 2 28.2 Example 3 8.1Example 4 21.6 Example 5 16.8 Example 6 24.1 Example 11 75.9 Example 1247 Example 13 5.9 Example 14 33.7 Example 15 6.8 Example 16 5.6 Example17 19.2 Example 18 30.7

[0211] As noted in the above table 1, the compounds of this inventionhave proven to have remarkable blood glucose lowering effects ondiabetes-induced rats.

EXPERIMENTAL EXAMPLE 2 Toxicity Test

[0212] The acute toxicity tests on rats were performed using thecompound prepared by the procedure of the Example 1. Mature ratsweighing 200-250 g were orally given the compound of the Example 1dissolved in ethylacetate in parallel with its gradually increasingconcentration. Then LD₅₀ was 487.1 mg/kg, which was calculated by numberof killed animals.

[0213] The test results was shown in the following table 2. TABLE 2Result of toxicity test number of killed animals/ dose concentration(mg/kg) number of animals per group 160 0/10 300 1/10 400 2/10 500 5/10600 8/10

1. A compound of the following formula 1 or a pharmaceuticallyacceptable salt thereof;

Wherein: A is one selected from the radicals expressed by the following(i), (ii), (iii) and (iv);

R₁ represents a lower alkyl. (wherein, R₂˜R₁₃ represent independentlyhydrogen, halogen, alkoxy, lower alkyl, hydroxy, alkenyl, alkynyl, cyanoor amino group; B is independently nitrogen or carbon; X is oxygen orsulfur; n denotes 0, 1 or 2).
 2. A compound of the formula 1 or apharmaceutically acceptable salt thereof according to claim 1, wherein:R is hydrogen, bromine or chlorine; R₃ is hydrogen, methyl, n-butyl, ormethoxy group; R₄ is hydrogen or methoxy group.
 3. A compound of theformula 1 or a pharmaceutically acceptable salt thereof according toclaim 1, wherein: R₅ is hydrogen or bromine; R₆ and R₇ are hydrogen. 4.A compound of the formula 1 or a pharmaceutically acceptable saltthereof according to claim 1, wherein: R₈ is hydrogen, methyl, chlorineor methoxy group; R₉ is hydrogen; R₁₀ is hydrogen or chlorine.
 5. Acompound of the formula 1 or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein: R₁₁ and R₁₃ are methyl; R₁₂ is hydrogen.6. A compound of the formula 1 or a pharmaceutically acceptable saltthereof according to claim 1, wherein R₁ is an ethyl group.
 7. Acompound of the formula 1 or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein n denotes
 0. 8. A compound of the formula1 or a pharmaceutically acceptable salt thereof according to claim 1,wherein n denotes
 1. 9. A process for manufacturing the compound of thechemical formula 1, wherein: a) 1,6-hexanediol of the structural formula2, a well known substance and starting material, is treated with sodiumhydride as a base to synthesize 6-benzyloxy-1-hexanol of the structuralformula 3 with substituted benzyl ring; b) The compound of the formula 3is tosylated to furnish the compound of the structural formula 4; c) Thecompound of the structural formula 4 is reacted with dimalonate tosynthesize dialkyl-6-benzoxihexylmalonate of the general formula 5; d)The compound of the general formula 5 is hydrolyzed using potassiumhydride to furnish the compound of the general formula 6; e)Eschernmorser's salt is added to the compound of the general formula 6to synthesize the alpha, beta-unsaturated ester of the general formula7; f) The compound of the general formula 7 is catalyzed by osmiumtetroxide to give the compound of the general formula 8; g) The compoundof the general formula 8 is further tosylated to synthesizealkyl-2-hydroxy-3-(4methylbenzenesulfoxy)-2-(6-benzoxy) hexylpropionicacid of the general formula 9; h) The compound of the general formula 9is treated with potassium carbonate as a base to givealkyl-2-(6-benzoxy)hexyloxiran-2-carboxylic acid of the general formula10, followed by the intermolecular cyclic reaction; i) The compound ofthe general formula 10 is hydrogenated to give the compound of thegeneral formula 11 with thereof benzyl group deprotected; j) Thecompound of the general formula 11 is treated with DCC, DMAP and methanedichloride and give oxirane carboxylic acid derivative of the formula 1,a desired compound, via esterification, etherification or amidoficationwith AH of the general formula. (wherein: A is the same as definedabove.)


10. An antidiabetic agent containing the compound or a pharmaceuticallyacceptable salt thereof expressed by the formula 1 according to claim 1.